HIV and HPV: What’s New for Men & Women Karla Maguire MD, MPH Jorge Garcia, MD Isabella Rosa-Cunha MD JoNell Potter PhD, RN University of Miami, Miller School of Medicine EPIDEMIOLOGY OF HPV AND HIV & SCREENING FOR CERVICAL CANCER KARLA MAGUIRE MD, MPH Financial Disclosures • None Objectives • Discuss HPV and its association with cancer • Describe the ways HPV is different in HIV positive women • Understand screening for cervical cancer in HIV negative and HIV positive women Human Papilloma Virus (HPV) • Common sexually transmitted infection • > 100 types – 40 infect cervix – 13 oncogenic (16, 18, 31, 33…) cancer – 6, 11 genital warts CDC Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected adults and adolescents, MMWR, 2009. HPV is common • Estimated Incidence: 6.2 million/year1 • Estimated prevalence: 20 million1 • Women 50 years of age: 80% will have acquired genital HPV infection2 • Sexually active,15-24 years old, currently infected: 9.2 million3 1. CDC National prevention Information network, 2004. 3. Weinstock H, Perspect Sex Reprod Health, 2004. 2. Cates W, Sex Transm Dis, 1999. HPV and HIV • HPV is more persistent in HIV positive women • Higher levels of HPV are detected in HIV positive women • Multiple HPV infections are more common in HIV positive women HPV and HIV - Persistence HPV Type HIV Positive : Persistent HPV Infection (%) HIV Negative : Persistent HPV Infection (%) High risk: HPV 16 associated 14.1 3.0 High risk: HPV 18 associated 8.2 0 Intermediate risk 6.4 0.9 1.8 0.4 24.1 3.9 Low risk Any Sun XW, NEJM, 1997. HPV and HIV - Persistence Jamieson DJ, AJOG, 2012. HPV and HIV – Higher levels Measure of Expression PCR signal intensity (3 or 4) Jamieson DJ, AJOG, 2012. HIV positive 80.6% HIV negative PR (95 CI) 62.6% 1.3 (1.1 – 1.5) HPV and HIV – Multiple infections Measure of Expression ≥ 2 HPV infections by PCR Jamieson DJ, AJOG, 2012. HIV positive 37.8% HIV negative PR (95 CI) 19.6% 1.9 (1.3 – 2.9) Audience Response Question • Which cancer is NOT associated with HPV infection? a) b) c) d) e) f) g) Cervix Vulva Vagina Ovary Penis Oral cavity Oropharynx CDC Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected adults and adolescents, MMWR, 2009. HPV • Persistent HPV infection can lead to: – Warts • Genital • Anal • Oral – Cancer precursors • • • • CIN VIN VAIN AIN – Cancer (squamous and adeno) • • • • • • Cervix Vulva Vagina Oral cavity Penis Oropharynx HPV Symptoms • Warts – Flat, papular, pedunculated growths – Millimeters to centimeters – Multiple or single – Asymptomatic, itching, discomfort • Cancer precursors – Asymptomatic • Cancer – Asymptomatic, bleeding, pain, mass CDC Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected adults and adolescents, MMWR, 2009. HPV and Cancer Anatomic site Total cancers* % estimated HPV attributable fraction† Cervix 11,820 100 Anus 4,187 85 Vulva/vagina 4,577 40 Penis 1,059 40 Oral/pharyngeal 29,627 15 * CDC. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices. MMWR 2007;56(No. RR-2):1–24. † Parkin M. Presented at the International Papillomavirus Conference, Vancouver, Canada, 2005 U.S. Cancer Statistics Working Group, http://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.pdf Audience Response Question • The incidence rate of cervical cancer in women with AIDS is how many times more than the general population? a) b) c) d) e) 2 3 5 9 20 Mbulaiteye SM, J Acquir Immune Defic Syndr, 2003. Cervical Cancer Screening • USPTF recommendations for routine screening Moyer VA, Ann Intern Med, 2012. Screening • However, these new recommendations do not apply to: – Women who have received a diagnosis of high grade precancerous cervical lesion or cancer – In utero exposure to DES – Immunocompromised women Moyer VA, Ann Intern Med, 2012. Screening • Screening for HIV positive women – Twice the first year after diagnosis – Annually thereafter CDC Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected adults and adolescents, MMWR, 2009. Screening • HIV positive women should be referred to colposcopy if their pap result is: – ASCUS – ASC-H – AGC – LSIL – HSIL • Currently insufficient evidence for use of HPV as an adjunct to testing CDC Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected adults and adolescents, MMWR, 2009. Screening Massad LS, JAIDS, 1999. Results of screening • Approximately 40 percent of HIV positive women will need follow-up with colposcopy! EVALUATION AND TREATMENT OF ANOGENITAL HPV INFECTIONS IN HIV POSITIVE WOMEN JORGE J GARCIA MD Objectives • Identify the clinical findings associated with anogenital HPV infections • Understand the histologic basis of abnormal colposcopic/anoscopic patterns • Discuss treatment options for managing anogenital intraepithelial neoplasia Goals of Anogenital Cancer Screening • Identify and treat high-grade cancer precursors. • Reduce a woman’s risk of developing invasive cancer. • Prevent unnecessary and potentially hazardous evaluations and treatment. • Minimize costs to healthcare system. Current Approach to Anogenital Cancer Prevention Requires 3 separate but linked components – Screening (cytology with or without HPV DNA testing) – Evaluation of screen positive women using colposcopy/anoscopy and biopsy – Treatment of women with biopsy-confirmed high-grade cancer precursors Wright T, Obst Gynecol, 2004. Hans Hinselmann http://commons.wikimedia.org/wiki/File.HansHinselmann.png Georgios N. Papanikolaou http://medicalhistory.blogspot.com Harald zur Hausen http://www.bestontop10.org/?p=636 Anogenital Cancer Screening Today • • • • • • Liquid media and sampling devices Bethesda Classification HPV testing New screening guidelines ASCCP algorithms Anal screening- no guidelines http://www.wcpl.com/physician_supplies.asp Evaluation • • • • • • Inspection Bimanual examination DRE (digital rectal examination) Colposcopy Digital imagining Biopsies Anatomy http://healthy-life-for-all.blogspot.com Clinical Findings http://genital-warts-medication.com Clinical Findings http://genital-warts-medication.com Clinical Findings http://genital-warts-medication.com Clinical Findings http://www.shifa2006.net Clinical Findings http://genital-warts-medication.com Bimanual Exam http://www.epubbud.com/read.php?g=XWL9CAZ3&p=1 DRE (digital rectal exam) http://artofanesthesia.blogspot.com Colposcopy • Localize the T-zone (squamo-columnar junction. • Evaluate the extent of the disease. • Locate the area most suspicious (for biopsy). • Determine if invasive cancer exists. Colposcope http://screening.iarc.fr/colpo.php http://screening.iarc.fr/colpo.php Audience Response Question Acetic acid has all of the following properties except: a) Coagulates and clears the mucous b) Causes swelling of tissue c) Is glycophilic d) Causes a reversible coagulation and precipitation of the nuclear proteins and cytokeratins • Reversible precipitation of nuclear proteins and cytokeratins. – Reaction known as Acetowhitening. – Directly related to the nuclear density Vazquez E. General Principles of Colposcopy, Residents Academic Day 7/22/2010 #7 • • • • Mature squamous epithelium = glycogen CIN and invasive Cancer = no glycogen Iodine is glycophilic No uptake looks yellow (mustard color) Vazquez E. General Principles of Colposcopy, Residents Academic Day 7/22/2010 #7 Colposcopy Normal Cervix http://screening.iarc.fr/colpo.php Squamocolumnar Junction • Intersection between cervical glandular columnar epithelium and squamous epithelium • Exposed columnar epithelium undergoes gradual replacement by squamous epithelium (squamous metaplasia)= Transformation Zone • Location of neoplastic change • Important landmark for colposcopy Auerbach R, www.coopersurgical.com/pages/residencyprograms.aspx Stratified Squamous Epithelium Vazquez E. General Principles of Colposcopy, Residents Academic Day 7/22/2010 #7 Dysplasia Vazquez E. General Principles of Colposcopy, Residents Academic Day 7/22/2010 #7 Colposcopic Findings The colposcopic diagnosis of cervical neoplasia depends on the recognition of four main features: • Intensity (color tone) of acetowhitening • Margins and surface contour of acetowhite areas • Vascular features • Color changes after iodine application Aceto-White Epithelium Auerbach R, www.coopersurgical.com/pages/residencyprograms.aspx Normal Vascular Patterns http://screening.iarc.fr/colpo.php Abnormal Vascular Patterns Auerbach R, www.coopersurgical.com/pages/residencyprograms.aspx Punctations Auerbach R, www.coopersurgical.com/pages/residencyprograms.aspx Mosaicism Auerbach R, www.coopersurgical.com/pages/residencyprograms.aspx Schiller’s test Vazquez E. General Principles of Colposcopy, Residents Academic Day 7/22/2010 #7 Cervical Biopsy http://screening.iarc.fr/colpo.php Audience Response Question All of the following are treatment options for cervical dysplasia except: a) Cryotherapy b) Trichloroacetic acid c) LEEP (loop electrocoagulation excision procedure) d) Laser vaporization e) CKC (cold knife conization) Cryotherapy http://screening.iarc.fr/colpo.php Loop Electrocoagulation Excision Procedure LEEP http://my.clevelandclinic.org Audience Response Question New technologies likely to play a significant role in anogenital cancer screening in the future are: a) p16 staining b) Digital imaging and computerized wavelength analysis c) Viral DNA methylation d) Anal cytology and anoscopy for high risk patients e) All of the above Anal Screening • Women with CIN, VIN, VAIN, and EGW may also present with AIN. • We should consider AIN as part of a multicentric disease of the lower genital tract . • Anal cytologic screening should be offered to these women. ANAL HPV AND HIV ISABELLA ROSA-CUNHA, MD Financial Disclosures • None OBJECTIVES • Anal Dysplasia and HIV • Screening anal dysplasia • Setting up anal dysplasia clinic Patel P et al. Annals of Int Med 2008. Johnson et al. Cancer 2004. Audience Response Question HIV-infected individuals at risk for anal dysplasia are… a) HIV-infected men who have sex with men. b) HIV-infected men and women engaging in anal sex. c) HIV-infected men and women. d) A+B. Piketty C et al. Ann Inter Med 2003. Holly E et al. J Natl Cancer Inst 2001. ANAL HPV DISEASE ANAL HPV INFECTION CONDYLOMA ANAL INTRAEPITHELIAL NEOPLASIA AIN I,II,III ANAL CANCER ANAL INTRAEPITHELIAL NEOPLASIA (AIN) •IN A STUDY FROM SAN FRANCISCO 277 HIV-positive, 211 HIV-negative MSM 4 year follow up Baseline anal cytology: normal, ASCUS or Low grade dysplasia. 49% HIV-positive progressed to high grade dysplasia. 17% HIV-negative progressed to high grade dysplasia. •IN A STUDY FROM SEATTLE 158 HIV-positive, 147 HIV-negative MSM No anal dysplasia at baseline 21 months follow up 15% HIV-positive developed high grade dysplasia. 5 % HIV-negative developed high grade dysplasia. Palefsky AIDS 1998; Critchlow AIDS 1995. CERVICAL/ANAL CANCER •Caused by HPV. •Arise at the transitional zone from columnar to squamous epithelium. http//www.lab.anhb.uwa.edu. Anal cancer like cervical cancer is a potentially preventable disease… Audience Response Question Does your HIV practice offer anal dysplasia/cancer screening? a) Yes b) No Mbulaiteye SM, J Acquir Immune Defic Syndr, 2003. There are no national and/ or international guidelines… •New York HIV Clinical guidelines In order to receive state or Federal HIV funding, health centers must perform routine anal pap smear in HIV-infected individuals: MSM, h/o anogenital condyloma and women with abnormal cervical and/or vulvar histology. •Newly established society International Anal Neoplasia Society (IANS). http://ians.memberlodge.org www.ucsfhealth.org/images/doctors Joel Palefsky, MD. UCSF Medical Center Anal Pap Smear Screening Chin-Hong and Palefsky 2006. DRE (digital rectal exam) http://artofanesthesia.blogspot.com. ANAL PAP SMEAR Liquid Media Polyester Swab Pennsylvania/MidAtlantic AETC. Anal Pap Smear: A Simple, Fast and Easy Procedure Source: Pennsylvania/MidAtlantic AETC Instructional video on performing anal Pap smears. Available on CD-ROM. Call the Johns Hopkins Local Performance site to order: 888-333-2855 (toll-free). ANAL CYTOLOGY http://5minuteconsult.com Bethesda Criteria: no malignant cells, AS-CUS, LSIL, HSIL. Adam et al. Gynecol Oncol 2012. ANAL CYTOLOGY •Sensitivity- 69% to 93% •Specificity- 32% to 59% Palefsky et al. J Acquir Immune Defic Synd Hum Retrovirol 1997; Mathews et al. J Acquir Immune Defic Syndr 2004; Lee et al. Int Conf AIDS 2004; Panther et al. CID 2004; Fox et al. Sex Transm Infect 2005; Salit at al. Annual Conference in Retroviruses and Opportunistic Infections 2005. AIDS Reader 2009. vol19 No5. HISTOLOGY Low-grade squamous lesion (LGAIN) AIN I (mild dysplasia) AIN II (moderate dysplasia) High-grade squamous lesions (HGAIN) AIN III (severe dysplasia or carcinoma in situ (CIS)) TREATMENT •Patient-applied: 5% imiquimod 0.5% podofilox gel 5% fluoracil cream •Clinician-applied: Cryotherapy Infra red coagulation Electrocautery Laser ablation COST- EFFECTIVENESS •Anal cytology has previously been shown to be a cost-effective screening method for the detection of squamous intraepithelial lesions in populations at high-risk for developing anal carcinoma. •Annual screening of HIV-positive MSM with anal Pap tests provided an incremental cost-effectiveness ratio of $16,600 per quality-adjusted life year saved. •This ratio is comparable with other widely accepted screening procedures, such as screening for colon cancer in the general population. Goldie SJ et al. JAMA 1999; 281:1822–1829; Inadomi. Curr Opin Gatroenterol 2003. DOES IT MAKE A DIFFERENCE? Chiao EY et al. CID 2006: 43(15 July). CERTIFICATION •Currently there are no national and/or international specific requirements or board certification to perform HRA. •You will need to work with your institution to request privilege. •There are colposcopy and HRA courses by ASCCP. BILLING There is no billing code for a visit for anal cytology collection. There are billing codes for the cytology billing: 88108 for liquid based cytology. 88104 for conventional brushing. 88160 for anal-rectal smears using Dacron® swab. 88112 for selective cellular enhancement technique with interpretation. BILLING High resolution Anoscopy CPT Codes: Category I 46600- Anoscopy w/wo collection specimen. 46606- Anoscopy w/Biopsy, single or multiple. Category III 0226T- anoscopy High Resolution w/specimen collection. 0227T- anoscopy High Resolution w/biopsy. The goal of screening is to detect anal dysplasia early and eradicate AIN, preventing the progression of such lesions to invasive squamous cell carcinoma. The optimum use of HPV testing, alternative screening methods and impact of HPV vaccination on anogenital HPV infection are yet to be defined. A heighted awareness of anal cancer among HIV-infected individuals is warranted and anal health should be an issue of priority in HIV care. Thank you!